Synthesis of certain 1-(1-methylpiperidin-4-y1)-3-phenylpyrazolo[4,3-C]pyridines

ABSTRACT

There are disclosed novel pyrazolo[4,3-c]pyridines of the formula &lt;IMAGE&gt;  where Ar and R1 are as defined in the specification, which are useful as serotonin reuptake inhibitors and as such may be useful for the treatment of depression, obsessive-compulsive disorders, stuttering and trichotillomania.

This is a division of prior application Ser. No. 08/106,953, filed Aug.17, 1993, now U.S. Pat. No. 5,296,491, which is a division of a priorapplication Ser. No. 07/964,690, filed Oct. 22, 1992, now U.S. Pat. No.5,264,576.

The present invention relates to compounds of the general formula##STR2## R₂ is hydrogen or loweralkyl; R₃ is hydrogen or loweralkyl;

R₄ is hydrogen or loweralkyl;

X and Y are independently hydrogen, halogen, trifluoromethyl, nitro,loweralkyl, loweralkoxy or hydroxy;

n is 1, 2 or 3;

m is 1 or 2;

p and q are independently 2, 3 or 4;

or a pharmaceutically acceptable addition salt and/or hydrate thereof,or where applicable, a geometric or optical isomer or racemic mixturethereof.

This invention also relates to a process for making the compounds and topharmaceutical compositions, and methods of use as serotonin reuptakeinhibitors.

The compounds of this invention are useful as serotonin reuptakeinhibitors and as such may be useful for the treatment of depression,obsessive-compulsive disorders, stuttering and trichotillomania.

Unless otherwise stated or indicated, the following definitions shallapply throughout the specification and appended claims.

The term lower shall mean the group it is describing contains from 1 to6 carbon atoms.

The term loweralkyl shall mean a straight or branched alkyl group havingfrom 1 to 6 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, pentyl and hexyl.

The term halogen shall mean fluorine, chlorine, bromine or iodine.

Throughout the specification and amended claims, a given chemicalformula or name shall encompass all stereo and optical isomers wheresuch isomers exist.

Additionally, a given chemical formula or name shall encompasspharmaceutically acceptable addition salts thereof and solyates thereof,such as hydrates.

In a preferred embodiment of this invention are compounds of the formula##STR3## wherein X and Y are independently hydrogen, halogen,trifluoromethyl, loweralkyl, loweralkoxy, nitro or hydroxy;

n is 1, 2 or 3;

m is 1 or 2; and

p is 2, 3 or 4.

More preferably, X is hydrogen, halogen, loweralkyl, loweralkoxy,trifluoromethyl or nitro and Y is hydrogen, halogen, loweralkyl,loweralkoxy or trifluoromethyl.

Most preferable are compounds wherein

X is Cl, Br, F, 4-CF₃, 2-CH₃, 4-NO₂ or 2-OCH₃ ; and

Y is hydrogen or Cl.

In another preferred embodiment of the invention are compounds of theformula ##STR4## wherein X and Y are independently hydrogen, halogen orCF₃.

More preferably X is halogen or CF₃ and Y is hydrogen or halogen.

Most preferable are compounds wherein

X is Br or Cl and

Y is hydrogen.

In a third preferred embodiment of the invention are compounds of theformula ##STR5## wherein R₄ is hydrogen or loweralkyl;

X and Y are independently hydrogen, halogen or trifluoromethyl and

q is 2,3 or 4.

More preferable are compounds of this embodiment

wherein

R₄ is hydrogen or methyl;

X is hydrogen or Cl;

Y is hydrogen or Cl; and

q is 2.

Also encompassed by this invention are intermediate compounds of theformula ##STR6## wherein X and Y are independently hydrogen, halogen,trifluoromethyl, loweralkyl, loweralkoxy, nitro or hydroxy.

More preferably, X is hydrogen or halogen; and

Y is hydrogen.

The compounds of this invention are prepared in the following manner.The substituents X, Y, R₁, R₂, R₃, R₄, n, m, p and q are as definedabove unless indicated otherwise.

PREPARATION

4-Chloropyridine of the formula ##STR7## is reacted with a solution oflithium diisopropylamine and tetrahydrofuran. This reaction typicallytakes place in a solution of tetrahydrofuran or other suitable solventat a temperature of about -80° to -40° C. for 2 to 6 hours. Afterstirring for 2 to 6 hours, a solution of a benzaldehyde or substitutedbenzaldehyde in tetrahydrofuran is added to give a compound of theformula ##STR8##

Compound VI in suspension with toluene or other suitable solvents and anoxidizing agent such as manganese (IV) oxide is refluxed for about 1 to4 hours to give compound VII of the formula ##STR9##

Compound VII is subsequently treated with hydrazine hydrate and refluxedfor 1 to 4 hours to yield a compound VIII of the formula ##STR10##

To prepare compound II of the formula ##STR11## where X, Y, n, m and pare as previously defined, compound VIII in suspension withdimethylformamide or other suitable liquid is reacted with a2-haloalkylphthalimide and a strong base such as potassium carbonate,sodium hydride or potassium t-butoxide. This mixture is reacted, withstirring, for 1 to 10 hours at 25° to 100° C. to give the phthalimido(alkyl) pyrazole pyridine of the formula ##STR12##

Compound IX is subsequently warmed in hydrazine hydrate to remove thephthalimide moiety to yield the desired compound.

To prepare compound X of the formula ##STR13## of the formula, where R₂and R₃ are loweralkyl, compound V is suspended in DMF or other suitableliquid and a strong base such as sodium hydride, potassium carbonate orpotassium t-butoxide. After stirring for 30 to 120 minutes, adialkylaminoalkyl chloride is added and the solvent is warmed to about25° to 100° C. with continued stirring. After 1 to 6 hours, compound Xis formed.

To prepare compound XI of the formula ##STR14## where R₃ is loweralkyl,compound II is reacted with methyl trifluoroacetate and anon-nucleophilic base such as triethylamine to yield compound XII of theformula ##STR15##

Compound XII with potassium t-butoxide or other suitable base is treatedwith dimethylsulfate or other suitable alkylating agent to yieldcompound XIII of the formula ##STR16## This reaction typically takesplace in a polar aprotic solvent such as tetrahydrofuran orN,N-dimethylformamide at a temperature of about 0° to 50° C. for 1 to 4hours.

Compound XIII is subsequently stirred in a mixture of methanol andsaturated potassium carbonate solution to yield the desired compound.

In order to prepare compound IV of the formula ##STR17## compound V indimethylformamide or other suitable solvent is reacted with a1-(2-haloalkyl)imidazole of the formula ##STR18## and potassiumcarbonate. The 1-(2-haloalkyl)imidazole is prepared as described inFoguet Ambros, R., Forne Felop, E., Ortiz Hernandes, J. A., Span. ES532,874, Oct. 1, 1985. This reaction typically takes place at atemperature of about 50° to 120° C. for 1 to 5 hours.

To prepare compounds where Ar is pyridyl, compound V, where Ar ispyridyl, is reacted as previously described in the preparation ofcompound II. The starting 3-(4-pyridyl)-1H-pyrazolo[4,3-c]piperidine canbe prepared as described for compound VIII usingpyridine-4-carboxaldehyde instead of benzaldehyde.

To prepare compounds where R₁ is methyl piperidine, compound XV of theformula ##STR19## is reacted with compound XVI of the formula ##STR20##and titanium isopropoxide to yield compound XVII of the formula##STR21## Compound XVI is prepared as described in Ebnother, A., Jucker,E., Lindenmann, A., Rissi, E., Steiner, R, Suess, R., Vogel, A. Helv.Chim. Acta, 42, 533 (1959). This reaction is typically conducted in aninch solvent such as dichloromethane or toluene at a temperature ofabout 0° to 50° C. for 12 to 72 hours. The hydrazone intermediate formedof the formula ##STR22## is reacted in tetrahydrofuran with potassiumt-butoxide at about 0° to 50° C. for 0.5 to 4 hours.

Finally, to prepare compound XIX of the invention of the formula##STR23## compound V is reacted with potassium carbonate or othersuitable base and a ω-haloalkyl piperidine to yield compound XIX.

This reaction is typically conducted at a temperature of about 50° to120° C. for 1 to 5 hours.

The compounds of the present invention may be useful for the treatmentof depression and/or obsessive competitive disorder by virtue of theirability to inhibit the reuptake of serotonin.

[³ H]-SEROTONIN UPTAKE IN RAT WHOLE BRAIN AND HYPOTHALAMIC SYNAPTOSOMES

Some researchers have suggested that subjects with serotonergichypofunction comprise a biochemical subgroup of depressed patients.Others claim that altered serotonergic function determines the changeassociated with obsessive-compulsive disorder.

This activity is determined in an assay which measures [³ H]-serotoninuptake in rat whole brain and hypothalamic synaptosomes. The assaydescribed below is used as a biochemical screen for potentialantidepressants which block serotonin (5-hydroxytryptamine (5HT))uptake.

[³ H]-5HT transport has been characterized in the central nervous systemtissue and found to be saturable, sodium and temperature-dependent,inhibited by ouabain, metabolic inhibitors, tryptamine analogs andtricyclic antidepressants.

Procedure

A. Animals

Male CR Wistar rats (100-125 g)

B. Reagents

1. Krebs-Henseleit Bicarbonate Buffer, pH 7.4 (KHBB):

Prepare a 1 liter batch containing the following salts.

    ______________________________________                                                        grams/l mM                                                    ______________________________________                                        NaCl              6.92      118.4                                             KCl               0.35      4.7                                               MgSO.sub.4.7H.sub.2 O                                                                           0.29      1.2                                               KH.sub.2 PO.sub.4 0.16      2.2                                               NaHCO.sub.3       2.10      24.9                                              CaCl.sub.2        0.14      1.3                                               Prior to use add to 200 ml, per assay:                                        Dextrose            2 mg/ml 11.1                                              Iproniazid phosphate                                                                            0.30 mg/ml                                                                              0.1                                               ______________________________________                                    

The batch is aerated for 60 minutes with 95% O₂ /5% CO₂, the pH ischecked to insure it is at 7.4±0.1, then add bovine serum albumin (Sigmacat# A-7906) 1 mg/ml.

2. Filtration buffer:

Make a 4 liter batch, containing the following salts:

    ______________________________________                                                      grams/4L                                                                              mM                                                      ______________________________________                                        NaCl            31.68     135.5                                               KCl             1.40      4.7                                                 MgSO.sub.4.7H.sub.2 O                                                                         1.16      1.2                                                 HEPES           9.54      10.0                                                CaCl.sub.2      0.56      1.3                                                 BSA             4.0       1 mg/ml                                             ______________________________________                                    

Maintain on ice.

3. Sucrose solution: 0.32M sucrose containing 5 mM HEPES and 0.1 mMEDTA; pH to 7.3 using Tris base.

4. A 0.1 mM stock solution of serotonin creatinine SO₄ is made up in0.01N HCl. This is used to dilute the specific activity of theradiolabeled 5HT.

5. 5-[1,2-³ H(N)]-Hydroxytryptamine creatinine sulfate (serotonin),specific activity 20-30 Ci/mmol, is used.

The final desired concentration of [³ H]-5HT in the assay is 50 nM. Thedilution factor is 0.8. The KHBB is made up to contain 62.5 nM of [³H]-5HT.

Add to 100 ml of KHBB.

    ______________________________________                                        A)       56.1 μl of 0.1 mM 5HT                                                                      =     56.1 nM                                        B)       0.64 nmol of [.sup.3 H]-5HT                                                                   =      6.4 nM                                                                       62.5 nM                                        ______________________________________                                    

6. For most assays, a 0.5 mM stock solution of the test compound is madeup initially in either 10 μl of glacial acetic acid, 100 μl DMSO or 10μl of the recrystallization solvent, to which is added approximately 10ml of distilled water. Compounds are initially screened in duplicate at3 concentrations (10⁻⁸, 10⁻⁷ and 10⁻⁶ M) made up in water. For thosecompounds demonstrating activity at ≦10⁻⁷ in the initial screen, EC₅₀ sare determined from 7 concentrations: 10⁻⁹ through 10⁻⁶. Higher or lowerconcentration ranges may be used depending on the potency of thecompound. To ensure consistency, the standard chlomipramine is run witheach assay.

C. Tissue Preparation

The Percoll method for preparing synaptosomes has been modified fromNagy, A., Delgado-Escueta, A. V. J. Neurochem. 43, 1114 (1984) andDunkley, P. R., Jarvie, R. E., Heath, J. W., Kidd, G. J., Rostas, J. A.P. Brain Research 372, 115 (1986). Male Wistar rats are decapitated andthe brain rapidly removed. Whole brain (minus cerebellum) is weighed andhomogenized in 15 volumes of ice cold Sucrose solution using aPotter-Elvejhem homogenizer. The following procedures are performed onice. Homogenization should be done with 4-5 up and down strokes atmedium speeds (setting 4.5 to 5) to minimize synaptosome lysis. Thehomogenate is centrifuged at 1000 g (3000 rpm Sorvall SS-34 rotor) for10 minutes at 0°-4° C. The supernatant is removed and approximately 10ml per tube is carefully layered onto a discontinuous Percoll (Sigmacat# P-1644) gradient: 21% Percoll in Sucrose solution at the bottom (15ml per tube) and 10% Percoll in the middle ( 10 ml; colored with a fewdrops of phenol red for visibility).

The Percoll gradient tubes are carefully placed into a Beckman SW-28swinging bucket rotor and spun in a Beckman XL90 ultracentrifuge usingthe following program: speed, 11,000 rpm (15,000 g) for 30 minutes at 4°C.; slow acceleration and deceleration (acceleration setting 9;deceleration setting 3). Tubes are carefully removed, and the top layerand the top part of the middle (red) layer are discarded using a pasteurpipette. The synaptosomes are located in the white fluffy band at theinterface between the 10% and 21% Percoll layers. This is carefullyremoved, placed in a centrifuge tube, diluted with KHBB and spun at21,000 g (13,000 rpm, Sorvall SS-34 rotor). The pellet (synaptosomes) isresuspended in KHBB (10 vol per gram original brain wet weight; 1 brainminus cerebellum weighs approximately 1.2 g; 2.5 brains are needed pertypical assay).

D. Assay

    ______________________________________                                        800 μl     KHBB with [.sup.3 H]-5HT                                         20 μl     Vehicle or appropriate drug                                     200 μl     Tissue suspension concentration                                 ______________________________________                                    

200 μl of the tissue suspension are added to each of 24 tubes (at atime) containing the 20 μl of vehicle or drug on ice. Three minuteslater, 800 μl of KHBB containing [³ H]-5HT are added, and the tubes arevortexed. The rack containing the 24 tubes is moved from the ice bath toa water bath set at 37° C. The tubes are incubated for 5 minutes under95% O₂ /5% CO₂. Uptake is terminated by filtration through GF/B filterstrips using a Brandel cell harvester (filter strips are presoaked inice cold filtration buffer). Tubes are washed once with 5 ml of ice coldfiltration buffer. Filter disks are placed in scintillation vials towhich are added 10 ml of scintillation fluid (EcoScint). Filters areallowed to sit overnight before being counted.

For each assay, 3 tubes each are incubated with 20 μl of vehicle at both37° C. and 0° C. Active uptake is the difference between cpm taken up at37° C. and 0° C. Percent inhibition at each concentration is the mean oftwo deteminants. IC₅₀ values are derived from log probit analysis using#46 Litchfield and Wilcoxon I: confidence limits of IC₅₀ PharmacologicCalculation System--version 4.0.

    ______________________________________                                                                 5-HT Uptake                                          Compound                 IC.sub.50 (μM)                                    ______________________________________                                        Chlomipramine (ref.)     0.018                                                Fluoxetine (ref.)        0.048                                                1-(2-aminoethyl)-3-(2-bromophenyl)-1H-                                                                 1.53                                                 pyrazolo[4,3-c]pyridine dihydrochloride                                       1-(2-aminoethyl)-3-(2-methylphenyl)-1H-                                                                0.87                                                 pyrazolo[4,3-c]pyridine                                                       1-(2-aminoethyl)-3-(4-bromophenyl)-1H-                                                                 0.94                                                 pyrazolo[4,3-c]pyridine                                                       1-(3-aminopropyl)-3-(4-chlorophenyl)-                                                                  0.77                                                 1H-pyrazolo[4,3-c]pyridine dimaleate                                          1-(2-aminoethyl)-3-(4-trifluoromethyl-                                                                 1.24                                                 phenyl)-1H-pyrazolo[4,3-c]pyridine maleate                                    1-(2-aminoethyl)-3-(2,3-dichloro-                                                                      0.21                                                 phenyl)-1H-pyrazolo[4,3-c] pyridine fumarate                                  1-(3-aminopropyl)-3-(2,3-dichloro-                                                                     0.41                                                 phenyl)-1H-pyrazolo[4,3-c]pyridine fumarate                                   1-(2-aminoethyl)-3-(2,4-dichloro-                                                                      0.058                                                phenyl)-1H-pyrazolo[4,3-c]pyridine fumarate                                   1-(4-aminobutyl)-3-(2,4-dichloro-                                                                      0.095                                                phenyl)-1H-pyrazolo[4,3-c]pyridine dimaleate                                  1-(2-aminoethyl)-3-(3,4-dichloro-                                                                      0.21                                                 phenyl)-1H-pyrazolo[4,3-c]pyridine maleate                                    1-(3-aminopropyl)-3-(3,4-dichloro-                                                                     0.24                                                 phenyl)-1H-pyrazolo[4,3-c]pyridine maleate                                    1-(2-aminoethyl)-3-(2,3,4-trichloro-                                                                   0.049                                                phenyl)-1H-pyrazolo[4,3-c]pyridine fumarate                                   1-(3-aminopropyl)-3-(2,3,4-trichloro-                                                                  0.023                                                phenyl)-1H-pyrazolo[4,3,-c]pyridine fumarate                                  ______________________________________                                    

Antidepressant relief is achieved when the compounds of the presentinvention are administered to a subject requiring such treatment as aneffective oral, parenteral, or intravenous dose of from 1 to 100 mg/kgof body weight per day. It is to be understood, however, that for anyparticular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further understood that the dosages set forthherein are exemplary only and they do not, to any extent, limit thescope or practice of the invention.

Effective quantities of the compounds of the present invention may beadministered to a subject by any one of various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions.

The compounds of the present invention, while effective themselves, maybe formulated and administered in the form of their pharmaceuticallyacceptable acid addition salts for purposes of stability, convenience ofcrystallization, increased solubility and the like.

Preferred pharmaceutically acceptable addition salts include salts ofinorganic acids such as hydrochloride, hydrobromic, sulfuric, nitric,phosphoric and perchloric acids; as well as salts of organic acids suchas tartaric, citric, acetic, succinic, maleic, fumaric, and oxalicacids.

Effective quantities of the compounds of the present invention may beadministered to a subject by any one of various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The compounds of the present invention, whileeffective themselves, may be formulated and administered in the form oftheir pharmaceutically acceptable addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Preferred pharmaceutically acceptable addition salts include salts ofinorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric,phosphoric and perchloric acids; as well as organic acids such astartaric, citric, acetic, succinic, maleic, fumaric, and oxalic acids.

The active compounds of the present invention may be administeredorally, for example, with an inert diluent or with an edible carrier.They may be enclosed in gelatin capsules or compressed into tablets. Forthe purpose of oral therapeutic administration, the compounds may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gums and thelike. These preparations should contain at least 0.5% of active compoundbut may be varied depending upon the particular form and mayconveniently be between 4% to about 75% of the weight of the unit. Theamount of compound present in such composition is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 mgs of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel™, corn starch andthe like; a lubricant such as magnesium stearate or Sterorex®; a glidantsuch as colloidal silicon dioxide; and a sweetening agent such assucrose or saccharin or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring may be added. When the dosage unit formis a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as fatty oil. Other dosage unit forms maycontain other various materials which modify the physical form of thedosage unit, for example, as coatings. Thus tablets or pills may becoated with sugar, shellac, or other enteric coating agents. A syrup maycontain, in addition to the active compounds, sucrose as a sweeteningagent and certain preservatives, dyes and colorings and flavors.Materials used in preparing these various compositions should bepharmaceutically pure and non-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of theaforesaid compound, but may be varied between 0.5 and about 30% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 mgs of activecompound.

The solutions or suspensions may also include the following components;a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes or multiple dose vialsmade of glass or plastic.

Examples of the compounds of this invention include:

3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridine hydrochloride;

1-(2-aminoethyl)-3-phenyl-1H-pyrazolo[4,3-c]pyridine dihydrochloride;

1-[3-(dimethylamino)propyl]-3-phenyl-1H-pyrazolo[4,3-c]pyridinedihydrochloride;

1-[3-(dimethylamino)ethyl]-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridinedimaleate;

1-[3-(methylamino)propyl]-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridinedimaleate;

1-[2-(1H-imidazolyl)ethyl]-3-phenyl-1H-pyrazolo[4,3-c]pyridine;

1-(2-aminoethyl)-3-(4-pyridyl)-1H-pyrazolo[4,3-c]pyridine dimaleate;

1-(4-aminobutyl)-3-(4-pyridyl)-1H-pyrazolo[4,3-c]pyridine dimaleate;

1-(3-aminopropyl)-3-(4-pyridyl)-1H-pyrazolo[4,3-c]pyridine fumarate;

3-(3,4-dichlorophenyl)-1-(1-methyl-4-piperidinyl)-1H-pyrazolo[4,3-c]pyridine;

3-(4-trifluoromethylphenyl)-1-(1-methyl-4-piperidinyl)-1H-pyrazolo[4,3-c]pyridinesesquifumarate;

1-[3-(1-piperidinyl)propyl]-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridinedimaleate;

[3-phenyl-1H-pyrazolo[4,3-c]pyridin-1-yl]acetonitrile;

3-(2-bromophenyl)-1H-pyrazolo[4,3-c]pyridine;

3-(3-bromophenyl)-1H-pyrazolo[4,3-c]pyridine;

3-(2-chlorophenyl)-1H-pyrazolo[4,3-c]pyridine maleate;

3-(4-bromophenyl)-1H-pyrazolo[4,3-c]pyridine;

1-(2-aminoethyl)-3-(2-bromophenyl)-1H-pyrazolo[4,3-c]pyridinedihydrochloride;

1-(3-aminopropyl)-3-phenyl-1H-pyrazolo[4,3-c]pyridine dihydrochloride;

1-(3-aminopropyl)-3-(2-bromophenyl)-1H-pyrazolo[4,3-c]pyridinedihydrochloride;

1-[3-aminopropyl]-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridinedimaleate;

1-[2-aminoethyl]-3-(2-chlorophenyl)-1H-pyrazolo[4,3-c]pyridinesesquifumarate;

1-[3-(dimethylamino)propyl]-3-(2-bromophenyl)-1H-pyrazolo[4,3-c]pyridinedihydrochloride hemihydrate;

1-[2-(dimethylamino)ethyl)-3-(2-bromophenyl)-1H-pyrazolo[4,3-c]pyridinedihydrochloride hydrate;

1-[2-(dimethylamino)ethyl]-3-(3-bromophenyl)-1H-pyrazolo[4,3-c]pyridinedihydrochloride sesquihydrate;

1-[3-(dimethylamino)propyl]-3-(3-bromophenyl)-1H-pyrazolo[4,3-c]pyridinedihydrochloride hemihydrate;

1-[3-(dimethylamino)propyl]-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridinedimaleate;

1-[2-(methylamino)ethyl]-3-(4-bromophenyl)-1H-pyrazolo[4,3-c]pyridine;

1-[2-(methylamino)ethyl]-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridinesesquimaleate;

1-[3-(methylamino)propyl]-3-(4-bromophenyl)-1H-pyrazolo[4,3-c]pyridinedimaleate;

1-[3-(methylamino)propyl]-3-(2-bromophenyl)-1H-pyrazolo[4,3-c]pyridinesesquioxalate;

1-[2-(1H-imidazolyl)ethyl]-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridinedimaleate;

1-[2-(1H-imidazolyl)ethyl]-3-(3,4-dichlorophenyl)-1H-pyrazolo[4,3-c]pyridinedimaleate;

1-[2-(2-methyl-1H-imidazolyl)ethyl]-3-(3,4-dichlorophenyl)-1H-pyrazolo[4,3-c]pyridinedimaleate; and

1-[2-(2-methyl-1H-imidazolyl)ethyl]-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridinehemifumarate.

The following examples illustrate the preparation of some of thecompounds of the invention and are not to be construed as limiting theinvention disclosed herein. All temperatures are given in degreescentigrade (°C.) unless indicated otherwise.

EXAMPLE 1 3-(4-Chlorophenyl)-1H-pyrazolo-[4,3-c]pyridine Hydrochloride

To a chilled (acetone/CO₂) solution of lithiumdiisopropylamide.tetrahydrofuran (THF) (200 ml) in 250 ml THF was addeda solution of 4-chloropyridine in 35 ml THF. After stirring for 4 hours,a solution of 4-chlorobenzaldehyde in 60 ml THF was added. The solutionwas allowed to come to room temperature, then worked up with water andextracted twice with ethyl acetate. The combined organics were washedwith water and dried (saturated NaCl solution, MgSO₄). The solvents wereconcentrated and the resulting solid was triturated with ethyl ether togive 41.3 g of a solid.

A suspension of the alcohol (9.5 g) from the previous step and manganese(IV) oxide (6.5 g) in 150 ml toluene was refluxed for 1.5 hours.Filtration through celite and concentration of the solvents gave 9.1 gof the ketone as an oil.

A solution of the ketone (9.1 g) in 50 ml ethanol was treated with 4.4ml of hydrazine hydrate. After refluxing for 2 hours, the mixture waspoured into iced water and the resulting solid was filtered and rinsedwith water and ether to give 6.57 g of a solid. A 3.0 g portion wasrecrystallized from methanol to give 2.0 g of a solid which wassuspended in methanol, treated with an ethereal HCl solution andfiltered. The salt was crystallized out with additional ether to give1.95 g of a powder, m.p. 265° C. (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for                                                                             54.16% C   3.41% H  15.79% N                                     C.sub.12 H.sub.8 ClN.sub.3.HCl:                                               Found:       53.98% C   3.41% H  15.67% N                                     ______________________________________                                    

Following a procedure similar to that described in Example 1 ,thefollowing 3-(halophenyl)-1H-pyrazolo[4,3-c]pyridines are prepared.

    ______________________________________                                         ##STR24##                                                                                                     m.p. (°C.)/                           Example   X       Y     Salt     Recryst. Solv.                               ______________________________________                                        1A        2-Br    H              215.5-216.5                                                                   diethyl ether                                1B        3-Br    H     --       >250                                                                          water wash                                   1C        2-Cl    H     maleate  175-177                                                                       methanol-ether                               1D        4-Br    H     --       >250                                                                          water wash                                   ______________________________________                                    

EXAMPLE 2 1-(2-Aminoethyl)-3-phenyl-1H-pyrazolo-[4,3-c]pyridineDihydrochloride

3-Phenyl-1H-pyrazolo[4,3-c]pyridine (1.95 g) was suspended in 50 ml ofdimethylformamide to which 2-bromoethylphthalimide (2.54) and K₂ CO₃(1.4 g) had been added. This mixture was stirred and warmed at 90° C.for 4 hours and then an additional 1.25 g of 2-bromoethylphthalimide and0.7 g of K₂ CO₃ were added. After 2 more hours another 0.60 g of2-bromoethylphthalimide and 0.4 g of K₂ CO₃ were added and stirring andheating were continued for an additional 90 minutes. At the end of thistime, the reaction mixture was poured into H₂ O and the product filteredoff and dried to give 2.63 of3-phenyl-1-[2-(phthalimido)ethyl]-1H-pyrazolo[4,3-c]pyridine.

The phthalimide prepared above (4.60 g) was warmed at 55° C. in 20 ml ofhydrazinc hydrate for 1 hour. At the end of this time the mixture wasdistributed between H₂ O and ethyl acetate and the organic phase wasseparated. The aqueous phase was extracted twice more with ethyl acetateand the combined organic phase was dried and evaporated. Thedihydrochloride was formed in methanol and recrystallized frommethanol-diethyl ether to give 2.10 g, m.p. 295° (dec).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for                                                                             54.03% C   5.18% H  18.00% N                                     C.sub.14 H.sub.14 N.sub.4.2HCl:                                               Found:       53.76% C   5.20% H  17.70% N                                     ______________________________________                                    

Following a procedure similar to that described in Example 2 above,using an appropriate bromoalkylphthalimide, the following1-(2-aminoalkyl)-3-(phenyl or substituted phenyl)-1H-pyrazolo[4,3-c]pyridines are prepared.

    ______________________________________                                         ##STR25##                                                                                                        m.p. (°C.)/                        Example                                                                              X        Y      p   Salt     Recryst. Solv.                            ______________________________________                                        2A     2-Br     H      2   di-HCl   250 (dec)                                                                     methanol                                  2B     H        H      3   di-HCI   260 (dec)                                                                     methanol                                  2C     2-Br     H      3   di-HCl   >250                                                                          methanol                                  2D     4-Cl     H      3   dimaleate                                                                              146-149 (dec)/                                                                methanol-ether                            2E     2-Cl     H      2   sesqui-  197-198 (dec)/                                                       fumarate methanol                                  2F     4-Cl     H      2   dimaleate                                                                              150-152 (dec)/                                                                methanol-ether                            2F     3-Br     H      2   di-HCl   235/                                                                          methanol-ether                            2G     3-Br     H      3   di-HCl   >250/methanol                                                        hemihydrate                                        2H     4-Br     H      2     --     107.5-109/                                                                    ether                                     2I     4-Br     H      3   diHCl    >250/                                                                         methanol-ether                            2J     2-Cl     H      3   fumarate 150-153 (dec)/                                                                methanol-ether                            2K     3-Cl     4-Cl   3   maleate  191 (dec)/                                                                    methanol-ether                            2L     3-Cl     4-Cl   2   maleate  200 (dec)/                                                                    methanol                                  2M     3-Cl     4-Cl   4   maleate  172.5 (dec)/                                                                  methanol-ether                            2N     4-Cl     H      4   dimaleate                                                                              143-144 (dec)/                                                                methanol-ether                            2P     4-CF.sub.3                                                                             H      4   maleate  171 (dec)/                                                                    methanol-ether                            2Q     4-CF.sub.3                                                                             H      2   maleate  180 (dec)/                                                                    methanol                                  2R     4-CF.sub.3                                                                             H      3   maleate  174 (dec)/                                                                    methanol-ether                            2S     2-Cl     4-Cl   2   fumarate 246 (dec)/                                                                    methanol                                  2T     2-CH.sub.3                                                                             H      2   sesqui-  195-195.5 (dec)/                                                     fumarate methanol                                  2U     2-CH.sub.3                                                                             H      3   sesqui-  174-175/                                                             fumarate methanol                                                             hemihydrate                                        2V     2-Cl     4-Cl   3   dimaleate                                                                              75-77/                                                               hemihydrate                                                                            methanol-ether                            2W     2-F      H      3   dimaleate                                                                              152-153.5/                                                                    methanol                                  2X     2-F      H      2   fumarate 167.5 (dec)/                                                                  methanol-ether                            2Y     2-Cl     6-Cl   2   fumarate 195-196/                                                                      methanol                                  2Z     4-NO.sub.2                                                                             H      2   hemi-    233 (dec)/                                                           fumarate methanol                                  2AA    4-NO.sub.2                                                                             H      3   fumarate 213 (dec)/                                                                    methanol                                  2BB    2-Cl     6-Cl   3   fumarate 183-184/                                                                      methanol                                  2CC    2-Cl     3-Cl   2   fumarate 217 (dec)/                                                                    methanol-ether                            2DD    2-Cl     3-Cl   3   fumarate 170 (dec)/                                                                    methanol                                  2EE    2-Cl,    4-Cl   2   fumarate 250 (dec)/                                       3-Cl                         methanol                                  2FF    2-Cl,    4-Cl   3   fumarate 208 (dec)/                                       3-Cl                         methanol                                  2GG    2-OCH.sub.3                                                                            H      3   dimaleate                                                                              149-150/                                                                      methanol, ethyl                                                               acetate                                   2HH    2-OCH.sub.3                                                                            H      2   dimaleate                                                                              173-174 (dec)/                                                                methanol                                  ______________________________________                                    

EXAMPLE 31-[3-(Dimethylamino)propyl]-3-phenyl-1H-pyrazolo-[4,3-c]pyridineDihydrochloride

3-Phenyl-1H-pyrazolo[4,3-c]pyridine (3.90 g) was suspended in 50 ml ofdimethylformamide and 60% NaH (1.0 g) was added. After stirring for 90minutes, dimethylaminopropyl chloride (3.0 g) was added, and stirringwas continued for 1 hour. At the end of this time the reaction waswarmed to 55° and, after an additional 2 hours, an additional 0.50 g ofdimethylaminopropyl chloride was added. Warming and stirring wascontinued for 1 hour, after which time the reaction mixture wasdistributed between ether and H₂ O. The organic phase was dried,evaporated, and purified by flash chromatography (5% triethylamine-ethylacetate), giving an oil upon evaporation of the product-containingfractions. The hydrochloride was formed in ethereal HCl andrecrystallized from methanol-ether to give 3.76 g of product, m.p.237°-239°.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for                                                                             57.80% C   6.28% H  15.86% N                                     C.sub.17 H.sub.20 N.sub.4.2HCl:                                               Found:       57.76% C   6.53% H  15.70% N                                     ______________________________________                                    

EXAMPLE 41-[2-(Dimethylamino)ethyl]-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]-pyridineDimaleate

A mixture of 3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridine (3.47 g),potassium carbonate (2.4 g) and dimethylaminoethyl chloridehydrochloride (4.6 g) in 50 ml DMF was heated at 85° C. for 1 hour. Thereaction was quenched into iced water and extracted three times withethyl acetate. The combined organics were washed with water and dried(saturated NaCl, MgSO₄). The compound was purified via flashchromatography (5→10% triethylamine/ethyl acetate) to give 3.47 g of anoil. The oil was dissolved in methanol, treated with 2.1 equivalents ofmaleic acid and crystallized with ethyl ether to give 4.95 g of apowder, m.p. 134°-136° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for                                                                              54.09% C  4.73% H   10.51% N                                    C.sub.16 H.sub.17 ClN.sub.4.2C.sub.4 H.sub.4 O.sub.4 :                        Found:        54.07% C  4.69% H   10.45% N                                    ______________________________________                                    

Following a procedure similar to that described in Example 4, using anappropriate dimethylaminoalkylchloride, the following1-[ω-(dimethylamino)alkyl]-3-(phenyl or substitutedphenyl)-1H-pyrazolo[4,3-c]pyridines are prepared.

    ______________________________________                                         ##STR26##                                                                                              Salt/    m.p. (°C.)/                         Example X      Y     P    Hydrate  Recryst. Solv.                             ______________________________________                                        4A      2-Br   H     3    di-HCl/  120/methanol-                                                        hemihydrate                                                                            ethyl acetate                              4B      2-Br   H     2    di-HCl/  207/methanol-ether                                                   hydrate                                             4C      3-Br   H     2    di-HCl/  134-136/                                                             1.5 Hydrate                                                                            methanol-ether                             4D      3-Br   H     3    di-HCl/  138-140/                                                             hemi-    methanol-ether                                                       hydrate                                             4E      4-Cl   H     3    dimaleate                                                                              129-131 (dec)/                                                                methanol-ether                             4F      H      H     2    dimaleate                                                                              134-135/                                                                      methanol-ether                             4G      4-Br   H     3    dimaleate                                                                              129-130/                                                                      methanol-ether                             4H      4-Br   H     2    dimaleate                                                                              139-140/                                                                      methanol ether                             4I      2-Cl   H     3    fumarate 156-158 (dec)                                                                 methanol-ether                             4J      2-Cl   H     2    di-HCl/  205-207/methanol-                                                    .25 hydrate                                                                            ethyl acetate                              ______________________________________                                    

EXAMPLE 51-[3-Methylaminopropyl]-3-(4-chlorophenyl)-1H-pyrazolo-[4,3-c]-pyridineDimaleate

A mixture of1-[3-aminopropyl]-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridinedimaleate (3.3 g), methyl trifluoroacetate (1.27 ml) and triethylamine(1.9 ml) in 75 ml methanol was stirred at ambient temperature for 45minutes. Concentration of the mixture and trituration of the resultingsolid with ether gave 3.76 g of a powder, m.p. 122°-125° C.

A mixture of the trifluoroacetamide (3.19 g) and potassium t-butoxide(1.07 g) in 70 ml THF was treated with dimethyl sulfate (0.83 ml) Afterstirring at ambient temperature for 1 hour the reaction was quenchedwith aqueous ammonia and the aqueous was extracted three times withethyl acetate. The combined organics were washed with water and dried(saturated NaCl, MgSO₄). Concentration of the solvent gave 3.6 g of asolid which was used in the next step.

The methyl derivative was stirred for 45 minutes in a mixture of 50 mlmethanol and 50 ml saturated potassium carbonate solution. The mixturewas partitioned between ethyl acetate and water and the aqueous wasextracted twice with ethyl acetate. The combined organics were driedwith MgSO₄. The desired compound was purified via flash chromatography(dichloromethane, methanol, triethylamine; 18:1:1) to give 1.11 g of anoil. This oil was dissolved in methanol treated with 2.1 equivalents ofmaleic acid and crystallized with ethyl ether to give 0.979 g of apowder, m.p. 149°-150° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for                                                                              54.09% C  4.73% H   10.51% N                                    C.sub.16 H.sub.17 ClN.sub.4.2C.sub.4 H.sub.4 O.sub.4 :                        Found:        53.70% C  4.44% H   10.42% N                                    ______________________________________                                    

Following a procedure similar to that described in Example 5, using anappropriate starting primary amine, the following1-[methylaminoalkyl]-3-[substituted phenyl]-1H-pyrazolo[4,3-c]pyridinesare prepared.

    ______________________________________                                         ##STR27##                                                                    Starting                                                                             Ex.                    Salt/    m.p. (°C.)/                     Amine  #      X       Y   P   Hydrate  Recryst. Solv.                         ______________________________________                                        Ex. 2H 5A     4-Br    H   2    --      60-61/                                                                        ether-pentane                          Ex. 2F 5B     4-Cl    H   2   1.5 maleate                                                                            169-170 (dec)/                                                                methanol-ether                         Ex. 2I 5C     4-Br    H   3   dimaleate                                                                              153-154/                                                                      methanol-ether                         Ex. 2C 5D     2-Br    H   3   1.5 oxalate                                                                            117 (dec)/                                                                    methanol-ether                         Ex. 2A 5E     2-Br    H   2   1.5 fumarate                                                                           170-172/                                                                      methanol-ether                         Ex. 2F 5F     3-Br    H   2    --      71-72.5/ether                          ______________________________________                                    

EXAMPLE 6 1-[2-(1H-Imidazoyl)ethyl]-3-phenyl-1H-pyrazolo[4,3-c]pyridine

3-Phenyl-1H-pyrazolo[4,3-c]pyridine (2.93 g) was suspended in 30 ml ofN,N-dimethylformamide to which 1-(2-chloroethyl)imidazole (2.15 g) andK₂ CO₃ (2.3 g) had been added. This mixture was stirred and warmed at90° for 2 hours and then an additional 0.20 g of1-(2-chloroethyl)imidazole and 0.2 g of K₂ CO₃ were added. After anadditional 45 minutes, the reaction mixture distributed between H₂ O andethyl acetate and the organic phase was washed with water. Evaporationand trituration with ether gave 2.15 g of product afterrecrystallization from CH₂ Cl₂ -pentane, mp 123°-125°.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.17 H.sub.15 N.sub.5 :                                                   70.57% C  5.23% H  24.20% N                                    Found:         70.45% C  5.24% H  24.18% N                                    ______________________________________                                    

Following a procedure similar to that described in Example 6, using anappropriate 3-(4-phenyl or substitutedphenyl)-1H-pyrazolo[4.3-c]piperidine, the following 1-[2-(1H-imidazolylor methyl-1H-imidazolyl)alkyl-3-(phenyl or substitutedphenyl)-1H-pyrazolo[4,3-c]piperidines are prepared.

    ______________________________________                                         ##STR28##                                                                                                           m.p./                                                                Salt/    Recryst.                               EX.  X       Y      R.sub.4                                                                             q   Hydrate  Solvent                                ______________________________________                                        6A   4-Cl    H      H     2   dimaleate                                                                              155-156 (dec)/                                                                methanol-ether                         6B   3-Cl    4-Cl   H     2   dimaleate                                                                              140.5-141.5/                                                                  methanol/ether                         6C   3-Cl    4-Cl   CH.sub.3                                                                            2   dimaleate                                                                              146-148/                                                                      methanol-ether                         6D   4-Cl    H      CH.sub.3                                                                            2   hemifuma-                                                                              215-217 (dec)/                                                       rate     methanol-ether                         6E   H       H      CH.sub.3                                                                            2   di-HCl/.25                                                                             233-235/                                                             hydrate  methanol-ether                         ______________________________________                                    

EXAMPLE 7 1-(2-Aminoethyl)-3-(4-pyridyl)-1H-pyrazolo[4,3-c]-pyridineDimaleate

A mixture of 3-(4-pyridyl)-1H-pyrazolo[4,3-c]pyridine (3.0 g), potassiumcarbonate (3.17 g) and N-(2-Bromoethyl)-phthalimide (5.84) in DMF (70ml) was heated at 90° C. for one hour. The reaction was cooled, dilutedwith water and extracted with dichloromethane. The organics were washedwith water, dried (MgSO₄), and filtered over a column of florisileluting the product with ethyl acetate, then 5% triethylamine/ethylacetate. Concentration followed by trituration with diethyl etheryielded 4.56 g of the phthalimide derivative.

The derivative was boiled for 2.5 hours in ethanol (250 ml) containinghydrazine monohydrate (4.0 ml). The reaction was cooled, diluted withwater and extracted with dichloromethane. The organics were washed withwater and brine, dried (MgSO₄), concentrated, and triturated withdiethyl ether to yield 0.941 mg of product. The dimaleate was formedfrom methanol/diethyl ether, filtered, washed with diethyl ether, anddried under high vacuum and refluxing iso-propanol for 4.0 hours toyield 1.32 g of a solid, m.p. 149.5° C.(dec.).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for                                                                             53.50% C  4.49% H    14.86% N                                    C.sub.13 H.sub.13 N.sub.5.C.sub.8 H.sub.8 O.sub.8 :                           Found:       53.21% C  4.43% H    14.81% N                                    ______________________________________                                    

EXAMPLE 8 1-(4-Aminobutyl)-3-(4-pyridyl)-1H-pyrazolo-[4,3,c]-pyridineDimaleate

A mixture of 3-(4-pyridyl)-1H-pyrazolo[4,3-c]pyridine (4.0 g), potassiumcarbonate (2.96 g) and N-(4-bromobutyl)-phthalimide (6.05 g) in DMF (90ml) was heated at 90° for one hour. An additional 150 mg of potassiumcarbonate and 300 mg of the phthalimide was added and heating wascontinued for two hours. The reaction was cooled, diluted with water andextracted with ethyl acetate. The organics were washed with water, dried(MgSO₄), concentrated, and triturated with diethyl ether to yield 6.08 gof the phthalimide derivative.

The derivative was boiled in ethanol (200 ml) containing hydrazinemonohydrate (4.0 ml) for 2.5 hours and solvent wits removed bydistillation. The residue was diluted with water (150 ml) and extractedwith methylene chloride. The organics were washed with brine, dried(MgSO₄), and concentrated. The residue was adhered to florisil withmethanol and flash chromatographed (florisil; 1:1:18methanol/triethylamine/dichloromethane. The dimaleate was formed frommethanol/diethyl ether, filtered, washed with diethyl ether, and driedunder high vacuum and refluxing iso-propanol for 4.0 hours to yield 2.15g of a solid, m.p. 141° C.(dec.).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for                                                                             55.31% C  5.05% H    14.02% N                                    C.sub.15 H.sub.17 N.sub.5.C.sub.8 H.sub.8 O.sub.8 :                           Found:       55.09% C  5.07% H    14.17% N                                    ______________________________________                                    

EXAMPLE 9 1-(3-Aminopropyl)-3-(4-pyridyl)-1H-pyrazolo[4,3-c]-pyridineFumarate

A mixture of 3-(4-pyridyl)-1H-pyrazolo[4,3-c]pyridine (3.20 g),potassium carbonate (2.37 g) and N-(3-bromopropyl)-phthalimide (4.6 g)in DMF (72 ml) was heated at 90° C. for one hour. The reaction wascooled, diluted with water and extracted with ethyl acetate. Theorganics were washed with water, dried (MgSO₄), and filtered over acolumn of florisil eluting first with ethyl acetate and then 5%triethylamine/ethyl acetate. Trituration with diethyl ethyl yielded 5.17g of the phthalimide derivative.

The derivative was boiled in ethanol (200 ml) containing hydrazinemonohydrate (4.0 ml) for one hour and solvent was removed bydistillation. The residue was adhered to florisil with methanol andflash chromatographed (florisil; 1:1:18triethylamine/methanol/dichloromethane) to yield 3.57 g of crudeproduct. A portion of this product (1.77 g) was taken up in methanol andthe fumarate salt was formed. The salt was recrystallized (methanol,diethyl ether and H₂ O) and dried under high vacuum and refluxingxylenes overnight to yield 1.65 g of a solid, m.p. 200° C.(dec.).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for                                                                             58.53% C  5.18% H    18.96% N                                    C.sub.14 H.sub.15 N.sub.5.C.sub.4 H.sub.4 O.sub.4 :                           Found:       58.43% C  5.11% H    18.68% N                                    ______________________________________                                    

EXAMPLE 103-(3,4-Dichlorophenyl)-1-(1-methyl-4-piperidinyl)-1H-pyrazolo[4,3-c]pyridin

4-Chloro-3-(3,4-dichlorobenzoyl)pyridine (2.26 g),1-methylpiperidine-4-hydrazine (1.0 g) and titanium isopropoxide (2.27g) were stirred together overnight in 20 ml of dichloromethane. At theend of this time, thin layer chromatography showed some startingmaterial remaining, so an additional 1.0 g of1-methylpiperidine-4-hydrazine and 2.27 of titanium isopropoxide wereadded and the reaction mixture was stirred an additional 24 hours. Thereaction volume was diluted to 200 ml with dichloromethane and 5 ml ofH₂ O was added. This mixture was stirred for 15 minutes and theprecipitated salts were filtered off. The filtrate was washed withwater, dried, and evaporated to give 3.0 g of a solid whose ¹ H NMR wasconsistent with 4-chloro-3-(3,4-dichlorobenzoyl)pyridine1-methyl-4-piperidinylhydrazone.

The hydrazone prepared in this manner was dissolved in 25 ml oftetrahydrofuran and treated with 0.90 g of potassium t-butoxide. After30 minutes, the reaction mixture was distributed between H₂ O and ethylacetate and the organic phase was dried and evaporated. The residueobtained was triturated with ether to give 1.43 g of product. Thefiltrate was evaporated and further purified by flash chromotography(18:1:1, ethyl acetate:methanol:triethylamine) to yield an additional0.40 g of product. The combined product was recrystallized from MeOH--H₂O to give 1.50 g, m.p.: 179°-180° C.(dec.).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.18 H.sub.18 Cl.sub.2 N.sub.4 :                                            59.84% C 5.02% H  15.51% N                                   Found:           59.83% C 4.90% H  15.47% N                                   ______________________________________                                    

EXAMPLE 113-(4-Trifluoromethylphenyl)-1-(1-methyl-4-piperidinyl)-1H-pyrazolo-[4,3-c]pyridineSesquifumarate

4-Chloro-3-(4-trifluoromethylbenzoyl)pyridine (2.28 g),1-methylpiperidine-4-hydrazine (1.5 g) and titanium isopropoxide (3.3 g)were stirred together overnight in 20 ml of dichloromethane. At the endof this time, thin layer chromatography showed some starting materialremaining, so an additional 0.5 g of 1-methylpiperidine-4-hydrazine and1.1 g of titanium isopropoxide were added and the reaction mixturestirred an additional 24 hours. The reaction volume was diluted to 200ml with dichloromethane and then 5 ml of H₂ O was added. This mixturewas stirred for 15 minutes, and then the precipitated salts werefiltered off. The filtrate was washed with water, dried, and evaporatedto give 2.96 of a solid whose ¹ H NMR was consistent with4-chloro-3-(4-rifluoromethylbenzoyl)pyridine-1-methyl-4-piperidinylhydrazone.

The hydrazone prepared in this manner was dissolved in 50 ml of THF andtreated with 0.90 g of potassium t-butoxide. After 30 minutes, thereaction mixture was distributed between H₂ O and ethyl acetate and thenthe organic phase was dried and evaporated. The residue obtained waspurified by flash chromatography (18:1:1, ethylacetate:methanol:triethylamine) to yield 1.61 g of product as an oil.The oil was taken up in 20 ml of acetone to which 2.1 g of fumaric acidwas then added. The product was filtered off and recrystallized fromacetonitrile-H₂ O to give 1.21 g of the sesquifumarate, m.p.: 240°C.(dec.).

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for                                                                              56.18% C  4.71% H   10.48% N                                    C.sub.19 H.sub.19 F.sub.3 N.1.5C.sub.4 H.sub.4 O.sub.4 :                      Found:        55.99% C  4.61% H   10.38% N                                    ______________________________________                                    

EXAMPLE 121-[3-(1-Piperidinyl)propyl]-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridineDimaleate

A mixture of 3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]pyridine (2.57 g),potassium carbonate (3.3 g) and 3-chloropropyl piperidine hydrochloride(2.44 g) in 45 ml dimethylformamide was heated at 85° C. for 2 hours.The reaction was quenched into iced water and extracted three times withethyl acetate. The combined organics were washed with water and dried(saturated NaCl, MgSO₄). The compound was purified via flashchromatography (2→4% triethylamine/ethyl acetate) to give 3.6 g of anoil. This was dissolved in methanol, treated with 2.1 equivalents ofmaleic acid and the salt was crystallized out with ethyl ether to give5.22 g of a powder, m.p. 160°-162° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for                                                                              57.29% C  5.32% H   9.54% N                                     C.sub.20 H.sub.23 ClN.sub.4.2C.sub.4 H.sub.4 O.sub.4 :                        Found:        57.33% C  5.30% H   9.50% N                                     ______________________________________                                    

EXAMPLE 13 [3-Phenyl-1H-pyrazolo[4,3-c]pyridin-1-yl]acetonitrile

3-Phenyl-1H-pyrazolo[4,3-c]pyridine (5.85 g) was suspended in 75 ml ofDMF and 60% NaH (1.5 g) was added. After stirring for 90 minutes,chloroacetonitrile (2.64 g) was added, and stirring was continued for 1hour. At the end of this time, an additional 1.00 g ofchloroacetonitrile was added and stirring was continued for 1 hour. Thereaction mixture was then poured into H₂ O and the crude product wasfiltered off and purified by flash chromatography (50% ethylacetate/DCM). Evaporation of the product-containing fractions gave 4.90g of product. Analytically pure material was obtained byrecrystallization from ethyl acetate-pentane, m.p. 148°-149°.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        Calculated for C.sub.14 H.sub.10 N.sub.4 :                                                   71.78% C  4.30% H   23.92% N                                   Found:         71.96% C  4.18% H   23.97% N                                   ______________________________________                                    

We claim:
 1. A process for preparing a compound of the formula ##STR29##where X and Y are independently hydrogen, halogen, trifluoromethyl,nitro, loweralkyl, loweralkoxy or hydroxy; which comprises reacting acompound of the formula ##STR30## with 1-methylpiperidine-4-hydrazineand titanium isopropoxide in a suitable solvent to form a compound ofthe formula ##STR31## which is subsequently reacted withpotassium-t-butoxide in a suitable solvent to form the desired product.